AbstractObjective: This study reports the pharmacokinetics, tolerability, and safety of an intranasal fentanyl spray (INFS) in patients with cancer and breakthrough pain (BTP). Design: A randomized, open-label, two-period, crossover trial. Patients: Nineteen adult patients (mean 57.8 years) with BTP, receiving opioid treatment for chronic background pain, from clinical departments in Austria, France, and Norway entered and completed the study. Intervention: Patients were randomly assigned to receive one of six INFS dose sequences: 50/100, 100/50, 50/200, 200/50, 100/200, and 200/100 µg. INFS was administered as a single dose in one nostril. Each dose was separated by a minimum of 48 hours. Main outcome measure: Plasma fentanyl concentrations were measured by high-performance liquid chromatography and tandem mass spectrometry from blood samples obtained at 0 (predose) and frequently up to 300 minutes after INFS administration. Blood pressure, peripheral oxygen saturation, and respiratory rate were assessed eight times during each of the two treatment periods. Results: Mean fentanyl plasma concentrations increased in a dose-dependent manner, peaking for all fentanyl doses 9-15 minutes after INFS administration. Median Tmax values were 15, 12, and 15 minutes for the 50, 100, and 200 µg doses of INFS, respectively. Mean (SD) values for Cmax were 351 (±226), 595 (±400), and 1195 (±700) pg/mL, respectively, indicating dose-proportionality. Six patients (31.6 percent) experienced adverse events during the treatment period, the majority being mild in severity. Conclusion: INFS at doses of 50, 100, and 200 µg showed a short Tmax and was well tolerated in patients with cancer. These results support INFS use in patients with cancer suffering from BTP. Keywords: intranasal administration, fentanyl, pharmacokinetics
DOI 10.5055/jom.2010.0001

ArticleVariability of transdermal fentanyl metabolism and excretion in pain patients

AbstractBackground: The rising popularity of the fentanyl transdermal patch and the striking number of deaths attributed to its prescribed use have brought attention to the large variability of fentanyl metabolism and the need for predictive models to prevent toxicity.
Objective: The purpose of this study was to determine the amount of both intrasubject and intersubject variability in fentanyl metabolism and excretion, using urinary excretion data from patients with chronic pain prescribed the fentanyl transdermal patch.
Methods: Liquid chromatography tandem mass spectrometry analytical technique was used to quantitate fentanyl and norfentanyl concentrations in spot urine specimens, after incubation with glucuronidase. Descriptive statistics and graphical analysis were conducted using Microsoft Excel 2007. Analysis was conducted on 206 subjects with = 2 visits listing transdermal fentanyl as current medication. Outliers and subjects with no detectable levels of drug were excluded, resulting in subject populations of 200 (all subjects analyzed) and 166 (subjects with drug concentrations above the instrument detection limit for all visits). Results: The geometric mean metabolic ratio (MR) of norfentanyl to fentanyl was 6.2 × ÷ 2.4. A wide distribution was observed in total fentanyl load (1,000-fold) and MR (200-fold). The intersubject geometric standard deviation in MR was 2.4 (95% confidence interval [CI] for MR: 1-37) and the intrasubject geometric standard deviation was 1.8 (95% CI for MR: 2-20).
Conclusion: The level of intrasubject variability over time in the pharmacokinetics of the fentanyl patch is much greater than previously observed and may be due to variability in absorption, interference of metabolism by concomitant medications, and variable metabolism due to genetic polymorphisms. The variation in the MR between subjects and within subjects may explain the unpredictable adverse effects observed with use of transdermal fentanyl.
Keywords: fentanyl patch, metabolism, excretion
DOI: 10.5055/jom.2010.0002

ArticleOxycodone/acetaminophen at low dosage: An alternative pain treatment for patients with rheumatoid arthritis

AbstractObjectives: To assess efficacy and safety of the association oxycodone/acetaminophen (oxycodone/ acetaminophen) for pain treatment and disability improvement in patients with rheumatoid arthritis (RA).
Methods: Patients with RA (n _ 29), suffering from moderate to severe pain for more than 3 months, were included in the study, except those under RA therapy with biological drugs. The treatment started with oxycodone/acetaminophen at the dosage of 5 mg/325 mg, and then the dosage was titrated until the attainment of good pain relief. Antiemetic and laxative therapy was used for the prophylaxis of known opioid-related adverse events. Results: Patients continued their RA therapy without changing the dosages, reported reduced pain intensity and disease activity, and improvement of disability. Forty-two percent of patients had a good clinical response to oxycodone/acetaminophen treatment, according to European League against Rheumatism (EULAR) assessment criteria, and 50 percent of patients reached the American College of Rheumatology 20 percent improvement criteria (ACR20). At the end of the study, the mean (_SD) daily effective oxycodone/acetaminophen dose was 13.8 (_6.8) mg/720.4 (_291.0) mg. No serious adverse event was observed. Nausea, vomiting, and stipsis of mild-moderate intensity were the most common adverse events.
Conclusion: Oxycodone/acetaminophen at low dosages for the treatment of chronic pain in RA patients can be a good alternative to non-steroidal anti-inflammatory drugs (NSAIDs), allowing the reduction of their consumption, while keeping RA therapy stable.
Keywords: opioids, pain control, rheumatoid arthritis, association oxicodone/acetaminophen
DOI:10.5055/jom.2010.0003

ArticleThe effect of intravenous opioid patient-controlled analgesia with and without background infusion on respiratory depression: A meta-analysis

AbstractBackground: Although the addition of a background infusion for intravenous patient-controlled analgesia (IV-PCA) has been identified as a risk factor for the development of respiratory depression, this has not clearly been examined in a systematic fashion. The authors undertook a systematic review and meta-analysis of available randomized controlled trials (RCTs) to examine whether the addition of a background or continuous infusion to an IV-PCA regimen would be associated with an increased risk of respiratory depression.
Methods: Studies were identified by searching the National Library of Medicine’s PubMed database (1966 to November 30, 2008). Inclusion criteria were a clearly defined analgesic technique of demand-only IV-PCA versus IV-PCA utilizing both a demand dose and background infusion, opioid medication used, and randomized trials. Data were abstracted and analyzed with the RevMan 4.2.7 (The Cochrane Collaboration, 2004).
Results: The search yielded 687 abstracts from which the original articles were obtained and data abstracted with a total of 14 articles analyzed. There were 402 subjects in the continuous IV-PCA with demand group versus the 394 subjects in the demand-only IV-PCA group. Addition of a background infusion to the demand dose for IV-PCA with opioids was associated with a significant increased risk for respiratory depression (odds ratio [OR] = 4.68, 95% confidence interval [CI]: 1.20-18.21). Subgroup analysis revealed that this increased risk was seen in adult but not in pediatric patients.
Conclusions: Our meta-analysis indicates that the addition of a continuous or background infusion to the demand dose for IV-PCA is associated with a higher incidence of respiratory events than demand IV-PCA alone in adult but not in pediatric patients; however, our overall results should be interpreted with caution due to the relatively small sample size and the wide range of definitions for respiratory depression in studies examined.
Keywords: background infusion, continuous infusion, patient-controlled analgesia, postoperative pain, meta-analysis
DOI:10.5055/jom.2010.0004

ArticleWeaning of opioids and benzodiazepines at home after critical illness in infants: A cost-effective approach

AbstractObjective: To evaluate the feasibility of infants’ weaning of opioids and sedatives at home.
Design: Retrospective observational study.
Setting: Level 3 pediatric intensive care unit.
Patients: Neonates treated for congenital diaphragmatic hernia (CDH) with extra corporeal membrane oxygenation (ECMO).
Intervention: Eligible infants were discharged early and further weaned of analgesics and/or sedatives at home.
Results: Of the 30 neonates treated for CDH with ECMO from 2003 to 2005, 15 survived. Five of these were weaned at home, on the guidance of telephone contact once a week. The mean infusion rates of morphine and midazolam for these children were significantly higher than those for other infants. Weaning at home took 11, 42, 107, 173, and 180 days, respectively, in the resultant mean savings on hospitalization costs per patient amounted to €150,000.
Conclusions: The results indicate that home weaning reduced the length of hospital stay by a median of 107 days for the five infants in this study, and thereby considerably reduced healthcare costs. Parents need to be informed clearly about possible withdrawal symptoms and should consent in this strategy. The strategy of final weaning with the aid of weekly telephone consultations with a consultant pediatric intensivist was feasible for these parents.
Keywords: opioids, benzodiazepines, withdrawal symptoms, drug weaning, children
DOI:10.5055/jom.2010.0005

ArticleEffect of preoperative rectal indomethacin on postoperative pain reduction after open appendectomy

AbstractBackground: One of the major challenges faced by the treatment planning teams is how to manage postoperative pain. Previous studies agreed upon the effects of preoperative administration of nonsteroidal anti-inflammatory drugs on postoperative pain, but all have focused on patients with surgical noninflammatory diseases (ie, inguinal hernia or breast biopsy). The aim of this study was to evaluate the effects of rectal indomethacin on reducing postoperative pain in patients with acute appendicitis.
Methods: It is a simple randomized, clinical trial including 200 patients with acute appendicitis who were divided into two groups (A1 and A2). The case group (A1) received 100 mg rectal indomethacin during 2 hours before the operation. Pain intensity was assessed in all patients using a visual analog scale (VAS). Similarly, total dosage of meperidine analgesic medication and postoperative time to use of rescue analgesia were evaluated.
Results: Patients who received preoperative rectal indomethacin (A1) showed a significant reduction in the VAS score. Also, a reduction in total dose of meperidine and longer time to use of rescue analgesic medication were observed in A1 group. Conclusion: Preoperative administration of rectal indomethacin in acute appendicitis reduces postoperative pain.
Keywords: postoperative pain, indomethacin, appendectomy
DOI:10.5055/jom.2010.0006

ArticleCase Study. Use of sublingual methadone for treating pain of chemotherapy-induced oral mucositis

AbstractChemotherapy-induced and radiation-induced mucositis is a debilitating and often painful condition resulting in an inability to swallow, and thus inability to maintain adequate quality of life and overall functioning. To date, attempts on palliation of mucositis-related pain have primarily used topical anesthetic solutions and intravenous opioids; these approaches have achieved only limited success, particularly in oncology patients. The authors present a novel case of mucositis-related pain that is effectively treated with sublingual methadone. Sublingual methadone is an alternative to standard treatment options for mucositis-related pain and has unique pharmacokinetic and pharmacodynamic properties that make methadone a suitable agent for this pathology. These properties are addressed and discussed, as is the need for additional study to better understand the potential benefits, burdens, and risks that may be associated with this formulation of methadone when treating chemotherapy-induced and/or radiation therapy-induced mucositis in patients with cancer.
Keywords: mucositis, methodone, sublingual, esophageal, cancer
DOI:10.5055/jom.2010.0007

AbstractBackground: The 3-glucuronide metabolites of morphine and hydromorphone have been implicated as a causative factor for patients exhibiting myoclonus.
Objective: The primary goal of this study was to determine plasma levels of morphine-3-glucuronide (M3G) or hydromorphone-3-glucuronide (H3G) in patients demonstrating myoclonus and identify any trends or associations between the two.
Setting: Patients were recruited from San Diego Hospice and the Institute for Palliative Medicine’s inpatient unit.
Design: A prospective convenience sample comprised of 17 subjects, 12 with myoclonus and 5 without yoclonus. Analysis included demographic, metabolicand clinical variables. Plasma was assayed via high performance liquid chromatography for morphine, M3G, and morphine-6-glucuronide or hydromorphone and hydromorphone-3-glucuronide.
Results: No trends or associations were identified between plasma levels of M3G or H3G and myoclonus. Ratio levels of 3-glucuronide metabolite to their corresponding parent opioid were dramatically lower than anticipated.
Conclusion: In this small pilot study, it appears that the serum levels of metabolites M3G and H3G do not correlate with myoclonus.
Keywords: morphine-3-glucuronide, hydromorphone-3-glucuronide, opioid neurotoxicity, myoclonus morphine, hydromorphone
DOI:10.5055/jom.2010.0008

ArticleBreakthrough pain in community-dwelling patients with cancer
pain and noncancer pain, Part 1: Prevalence and characteristics

AbstractBackground: Most breakthrough pain (BTP) studies assess patients with
advanced cancer or those receiving inpatient care. Studies in noncancer populations are limited to surveys of pain clinics and patients with other advanced diseases. To better understand BTP, data are needed from less selected populations.
Aim: The aim of this study was to evaluate BTP in opioid-treated ambulatory patients with chronic cancer or noncancer pain treated in community practices.
Methods: Primary care physicians or community-based oncologists recruited a convenience sample for a cross-sectional study of BTP at 17 sites in the United States. Physicians could not be pain specialists. Patients were eligible if they had any type of pain for = 3 months and were receiving an opioid drug on a regular basis that controlled the pain. The patients responded to a structured interview comprising items that assessed the baseline pain and items that assessed BTP, if present.
Results: In total, 355 patients were screened, 191 were eligible and 177 (93 percent) provided data for analysis. Seventy-eight patients had cancer pain and 99 had noncancer pain. Patients with cancer were older (mean ± SD age 61.3 ± 11.2 years vs 51.4 ± 13.6 years, p < 0.001), and patients without cancer had more neuropathic pain (21 vs 12 percent, p < 0.05) and a longer pain duration (median 3.5 vs 1 years, p < 0.001). BTP occurred in 33 percent with cancer and 48 percent with noncancer pain (p = 0.042). BTP did not vary by diagnosis, but neuropathic pain was more common in those with BTP (27 vs 10 percent, p < 0.001). In patients with and without cancer, the median daily number of episodes was 1, the median time to maximum pain was 1-2 minutes, and the median duration was 45-60 minutes. There were fewer BTP precipitants in the patients with cancer (46 vs 80 percent of pains, p < 0.05), and they had less predictable pain (p < 0.05).
Conclusions: The prevalence of BTP among community-dwelling patients is lower than that found in prior studies of more selected populations. BTP is more prevalent among patients with noncancer pain than patients with cancer pain, and although there are many similarities, some differences may be relevant to treatment strategies.
Keywords: breakthrough pain, chronic pain, survey
DOI:10.5055/jom.2010.0009

ArticleBreakthrough pain in community-dwelling patients with cancer pain and noncancer pain, Part 2: Impact on function, mood, and quality of life

AbstractBackground: Prior studies of breakthrough pain (BTP) largely focus on patients with advanced cancer or those receiving inpatient care. Very few studies have evaluated BTP in populations with chronic noncancer pain. Data that illuminate the impact of BTP may not generalize to other, less selected patient populations.
Aim: The aim of this study was to evaluate the impact of BTP in opioid-treated ambulatory patients with chronic cancer pain or noncancer pain treated in community practices.
Methods: Eligible patients–those with any diagnosis who reported chronic pain for at least 3 months, who were receiving long-term opioid therapy, and who met criteria for controlled baseline pain–were recruited for a cross-sectional observational study by primary care physicians or community-based oncologists at 17 sites in the United States. The patients responded to a structured interview for breakthrough pain and also completed the Brief Pain Inventory-Modified Short Form (BPI-SF) and the Brief Battery for Health Improvement 2 (BBHI 2).
Results: Of 355 patients screened, 191 were eligible and 177 (93 percent) provided data for analysis. Twenty-six of the 78 with cancer pain (33 percent) and 48 of the 99 with noncancer pain (48 percent) had BTP. Compared with those without BTP, both patients with cancer (p = 0.004) and patients without cancer (p = 0.019) with BTP had increased pain interference in function, as measured by the BPI-SF, and patients without cancer were more impaired than patients with cancer. On the BBHI 2, BTP was associated with increased somatic complaints (p = 0.036 cancer and p = 0.024 noncancer) and pain complaints (p = 0.037 cancer and p = 0.037 noncancer); among patients without cancer, BTP was also associated with increased difficulties with functioning (p = 0.023), depression (p = 0.039), and decreased quality of life (p = 0.003).
Conclusions: These data extend published observations about the association between BTP and adverse effects on mood and function to populations undergoing routine treatment in the community setting and provide evidence that these associations are greater in those with noncancer pain. They suggest the need for additional studies to clarify causality and determine whether undertreatment of BTP is a factor contributing to adverse pain-related outcomes.
Keywords: breakthrough pain, chronic pain, functional impairment, psychological distress
DOI:10.5055/jom.2010.0010

ArticleUtility of transdermal fentanyl for prevention of iatrogenic opioid abstinence syndrome in children

AbstractBackground: Iatrogenic opioid abstinence syndrome (IOAS) can occur in critically ill infants/children following abrupt discontinuation of opioids. There are no standard guidelines for the prevention of IOAS. Transdermal fentanyl (TF) has been infrequently used at our institution for the prevention of IOAS.
Methods: This was a retrospective, descriptive study of children less than 18 years of age receiving TF for the prevention of IOAS. Baseline demographics, IV sedative/analgesic regimen, TF regimen, and IOAS symptoms were collected. The primary objective was to describe the TF regimen. The secondary objectives were to classify the number/type of withdrawal symptoms and to identify the number of intermittent opioids administered for withdrawal symptoms.
Results: Fifteen patients were identified with a median age of 7 years (0.3-17); the median cumulative IV fentanyl dose prior to initiation of TF was 1,356 µg kg-1 (164.1-9595.8). The median initial dose of TF was 1.9 µg kg-1 h-1 (0.4-6.1) or 25 µg h-1 (12.5-500); TF was continued for a median duration of 16 days (5-27). To provide the desired dose, the TF patch was partially covered with Tegaderm™ in eight patients. Eighty-six intermittent opioid doses were administered during TF therapy with 51 (59 percent) administered within 5 days of TF initiation. Seven patients (46.7 percent) had IOAS. No significant differences in IOAS symptoms were observed between patients whose patch was partially covered versus not covered, 3 versus 4, respectively (p > 0.05). There was no correlation between the number of opioid doses administered and IOAS symptoms from days 1 to 5, correlation coefficient 0.347 (p _ 0.206).
Conclusions: In this cohort, most patients required additional opioids for IOAS symptoms during the first 5 days of TF. TF therapy cannot be routinely recommended for the prevention of IOAS until further prospective studies can confirm these results. This pilot study highlights future directions to standardize documentation and to educate clinicians on IOAS symptoms.
Keywords: children, transdermal fentanyl, opioid withdrawal
DOI:10.5055/jom.2010.0011

AbstractObjective: Postoperative pain should be aggressively treated to decrease the development of chronic postsurgical pain. There has been an increase in the use of Human Patient Simulator (HPS) for teaching advanced courses in pharmacology to medical students, residents, and nurses. The aim of this educational investigation was to pilot the HPS for the training of medical students and surgical recovery room staff nurses in the pharmacology of opioids for the management of postoperative pain.
Methods: The computerized HPS mannequin is fully monitored with appropriate displays and includes a voice speaker mounted in the head. Medical students and Postanesthesia care unit nurses, led by faculty in the Department of Anesthesiology in small groups of 4-6, participated in a 2- to 3-hour HPS course on the use of opioids for the management of acute postoperative pain. Trainees were asked to treat the acute and severe postoperative pain of a simulated patient. Opioid effects and side effects (such as respiratory depression) were presented on the mannequin in real time to the participants. Side effects of naloxone to reverse opioid depression were presented as a crisis in real time to the participants. Participants completed a 10-item course evaluation using a 5-point Likert scale (1 = strongly disagree; 5 = strongly agree).
Results: Twenty-two nurses and nine medical students completed the HPS opioid pharmacology scenario. Almost all participants rated the HPS course very highly and rated every item as either agree or strongly agree. Most participants agreed that the simulator session improved their understanding of opioid pharmacology including opioid side effects and management of opioid complications. Course participants felt most strongly (median, interquartile range) that the simulator session improved their understanding of naloxone pharmacology (5, 0), simulators serve as a useful teaching tool (5, 0), and that they would be pleased to participate in any additional HPS teaching sessions (5, 0).
Conclusions: The HPS provides a novel educational format to teach essential information regarding opioid pharmacology for the management of acute postoperative pain. The HPS provides a realistic format to teach the pharmacology of acute opioid side effects and the management of acute and life-threatening side effects of naloxone therapy.
Keywords: patient simulation, resident education, opioid pharmacology, opioid pharmacodynamics, Human Patient Simulator, naloxone
DOI:10.5055/jom.2010.0012

AbstractPurpose: Data suggest an increase in prescription opioid abuse in recent years. Young veterans represent a group with major risk factors for prescription opioid abuse. The objectives of this study are: (A) to determine the prevalence of chronic opioid use in young veterans over time; (B) to describe the prescribing patterns and monitoring of chronic opioid therapy in young veterans; and (C) to assess opioid management within Veterans Affairs Palo Alto Health Care System (VAPAHCS) with an emphasis on effectiveness and safety.
Methods: This is a Veterans Affairs Research and Development (R&D) Committee and IRB-approved retrospective, single-center study of young veterans aged 18-30 years on chronic opioid therapy during the study years January 1, 2003, to October 1, 2008. A subset of the study population who were receiving long-acting opioids for a minimum of 6 months was included in the effectiveness and safety analyses. Data were obtained from the Veterans Integrated Service Network (VISN 21) data warehouse, outpatient prescription records, and from electronic chart review.
Results: The prevalence of chronic opioid use in young veterans has increased from 3 percent in 2003 to 4.5 percent in 2007. Patients on average were exposed to two different opioids and had three different opioid prescribers. Nearly 80 percent of the opioid prescriptions during the study were prescribed by primary care providers and less than 1 percent was from pain specialists. Only 31 percent of patients on chronic opioids had undergone urine drug testing and only 5 percent had signed opioid treatment agreements. No difference in median pain score was observed following initiation of long-acting opioid therapy, and 22 percent of patients (4 of 18) met the prespecified definition of being a responder to long-acting opioid therapy. Five patients (28 percent) on long-acting opioids experienced adverse drug reactions.
Conclusion: The prevalence of chronic opioid use in young veterans has been on the rise in recent years. Young veterans receiving care at VAPAHCS have often had multiple opioid prescribers and have trialed multiple opioid analgesics. Many improvements in appropriate monitoring and management of these patients can be made, which may include providing more training to current staff, the development of an opioid refill clinic, and greater utilization of the pain management specialists. Further larger study is warranted to identify successful strategies for improving prescribing and monitoring of opioids as well as potential predictors of response to chronic long-acting opioid therapy.
Keywords: opioids, veterans, pain, chronic, prevalence, monitoring, safety, efficacy
DOI:10.5055/jom.2010.0013

ArticleComparison of the postoperative analgesic efficacy of intravenous patient-controlled analgesia with tramadol to intravenous patient-controlled analgesia with opioids

AbstractBackground: Intravenous patient-controlled analgesia (IV PCA) with tramadol is an accepted method to deliver postoperative analgesia outside North America; however, the analgesic efficacy of this analgesic agent when compared with IV PCA with opioids is uncertain. As such, the authors undertook a systematic review to compare the analgesic efficacy of IV PCA tramadol with that of IV PCA with opioids.
Methods: The authors used the National Library of Medicine’s Medline database to search for terms related to tramadol and patient-controlled analgesia. Inclusion criteria were randomized controlled trials (RCTs) comparing IV PCA tramadol with IV PCA opioid and RCTs published in the English language. Relevant data were abstracted from accepted studies. Meta-analysis was performed using RevMan 4.2.10 (The Cochrane Collaboration, 2004). A random effects model was used.
Results: A total of 190 abstracts were obtained from the above search, and a total of 12 RCTs met the above inclusion criteria. There was no difference in weighted visual analog scale pain scores between IV PCA tramadol versus IV PCA opioid at 48 hours postoperatively or risk of sedation or fatigue. IV PCA tramadol was associated with a higher odds of postoperative nausea and vomiting [odds ratio (OR) = 1.52, 95% confidence interval (CI) = 1.07-2.14) but a lower odds of pruritus (OR = 0.43, 95% CI = 0.19-0.98).
Discussion: IV PCA tramadol appears to produce similar pain scores when compared with that from IV PCA opioids; however, the side effect profile is different between the two groups. Because of the relatively small sample size, no determination of the relative “safety” (eg, respiratory depression) of one regimen over the other can be made, and larger RCTs would be needed for such a determination.
Keywords: tramadol, patient-controlled analgesia, postoperative pain, meta-analysis
DOI:10.5055/jom.2010.0014

Journal of Opioid ManagementMay/June 2010, Volume 6, Number 3

ArticleLetter to the editor.
The abuse of prescription medications: A relationshup with borderline personality?

AbstractBackground: This multicenter, parallel-group, 35-day study in adults with osteoarthritis (OA) pain evaluated the analgesic efficacy and safety of buprenorphine transdermal system (BTDS) designed for 7-day wear.
Methods: Patients with OA pain inadequately controlled with nonsteroidal anti-inflammatory drugs or patients who had taken opioids for OA pain within the past year entered a 7-day run-in period during which they took ibuprofen only. Patients with pain = 7 on a 0-10 scale had their ibuprofen discontinued and were randomized into a 28-day double-blinded period to receive either BTDS at 1 of 3 dose levels (5, 10, or 20 µg/h) or placebo. Doses were titrated to effectiveness over a period of 21 days and maintained for 7 days. No rescue medication was allowed during the study. The primary efficacy measure was the proportion of patients who achieved treatment success, defined as a patient satisfaction score of good, very good, or excellent (on day 28 or at early discontinuation) for those who did not discontinue due to ineffective treatment.
Results: More BTDS-treated patients experienced treatment success than placebo TDS-treated patients (44 percent and 32 percent; odds ratio = 1.66, p = 0.036). Fewer patients taking BTDS titrated to the highest dose compared with placebo (p < 0.05). There were two serious adverse events (both in the placebo group) and no deaths. The most common (= 5 percent) adverse events reported in BTDS treated patients were nausea, headache, dizziness, somnolence, application site pruritus, and vomiting.
Conclusion: Compared with placebo, BTDS treatment was effective in treating patients with moderate to severe pain due to OA of the knee or hip. BTDS was well tolerated.
Keywords: buprenorphine, transdermal, pain, analgesia, osteoarthritis, randomized controlled trials
DOI:10.5055/jom.2010.0017

ArticleSafety and tolerability of fentanyl iontophoretic transdermal system:Findings from a pooled data analysis of four clinical trials

AbstractAcute postoperative pain remains inadequately managed. Although patient controlled analgesia (PCA) represents a significant advance in postoperative pain management, drawbacks may include invasiveness and the potential for programming errors. The analysis presented here is based on pooled patient-level safety data from four multicenter, randomized, active-controlled trials that evaluated the safety and tolerability of the needle-free, preprogrammed fentanyl HCl iontophoretic transdermal system (ITS) versus morphine intravenous PCA for postoperative pain management; the results for patients who received fentanyl ITS are presented here. Adverse events (AEs), serious AEs, and clinically relevant respiratory depression were assessed across patient subpopulations categorized by age. A total of 1,288 patients, including 356 elderly (> 65 years of age) patients, received fentanyl ITS following surgery. The most commonly reported AEs included nausea, fever, vomiting, headache, anemia, pruritus, and hypotension. The incidence of AEs was generally lower for elderly patients than for patients 65 years or younger. Application-site reactions were reported for 18.6 percent of patients using fentanyl ITS and were generally mild to moderate in severity. No cases of clinically relevant respiratory depression were eported for patients who received fentanyl ITS. The results demonstrate that fentanyl ITS is safe and well tolerated for postoperative pain management for patients overall and for subpopulations divided according to age.
Keywords: tolerability, pain management, postoperative, fentanyl ITS, patient-controlled analgesia
DOI:10.5055/jom.2010.0018

AbstractTapentadol hydrochloride (17(—)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol) is a newly released analgesic that works at two levels: by acting as a µ-opioid agonist and as a modulator of descending inhibitory pathways through its effects on neurotransmitters involved in these pathways. The theoretical advantage is the provision of synergistic analgesic activities, which may lessen the need for opioid escalation. The advantage is its potential as a possible new agent in neuropathic pain. Preclinical models confirm analgesic properties in acute pain and neuropathic pain models, but with less potency than morphine. Tapentadol has minimal CYP 450 interactions limiting potential for drug interactions. Human clinical trial data in nonmalignant pain suggest less potency than a step-3 opioid, and the drug remains to be tested in patients with cancer pain and neuropathic pain.
Keywords: tapentadol, affinity, neuropathic
DOI:10.5055/jom.2010.0020

AbstractBackground: Heroin use carries a large burden of morbidity and mortality. Heroin overdose and in particular events that need intensive care unit (ICU) admission have not been widely examined. The aim of this study was to describe the causes of ICU admission and the outcome of patients with a heroin overdose.
Methods: A retrospective chart review of all patients with a heroin overdose admitted to the ICU between 1987 and 2006 was conducted.
Results: Forty-two records were available for review. The average age of the patients was 28 years. In the field, 19 persons were found in coma Glasgow Coma Scale (GCS < 8) and respiratory depression and were treated with naloxone. The reasons for ICU admission included hypoxemia in 37 (88 percent), 28 of whom had acute lung injury (ALI) and nine aspiration pneumonia, shock in three (7.2 percent) and persistent mental compromise in two patients (4.8 percent). Intubation and mechanical ventilation (MV) were instituted in 37 patients. In 19 of the 37 patients, weaning and extubation became possible within the first 24 hours. Sixteen patients suffered complications and received MV for 5 ± 2 days, with a mean length of ICU stay of 8 ± 1 days, while two patients succumbed because of anoxemic encephalopathy and brain death. The complications observed were acute respiratory distress syndrome in eight patients, severe sepsis in four, catheter-related bacteremia in one, iatrogenic pneumothorax in one, and rhabdomyolysis in two, while four among them died due to severe sepsis.
Conclusions: In our study, ALI and aspiration pneumonia were the most frequently observed respiratory complications after acute heroin overdose requiring intubation and ICU admission. Mortality rate was 14.2 percent and was attributed to septic complications and irreversible brain damage.
Keywords: heroin overdose, acute drug intoxication, ICU management
DOI:10.5055/jom.2010.0021

AbstractResearch has raised the possibility that the length of time one engages in nonmedical use of prescription opioids may be associated with abuse of other drugs, more risky drug-related behavior, and more severe functional problems. This study drew on data from the Addiction Severity Index-Multimedia Version® Connect system. A total of 55,341 client assessments at substance abuse treatment centers were analyzed to help understand the impact of length of time one has abused opioids on the patterns of abuse and functional problems. From this larger sample, 5,686 individuals who had abused a prescription opioid within the past 30 days were studied. Multiple logistic regression analyses were run to examine the impact of length of time abusing any opioid, after adjusting for several demographic variables, on route of administration (injection or injection/snorting), other drugs abused, and functioning in the areas of medical status, employment, drug and alcohol use, legal status, family and social problems, and psychiatric status. Overall findings supported the hypothesis that length of opioid abuse is associated with higher risk of drug use patterns as well as functional problems.
Keywords: prescription opioids, drug abuse, route of administration, ASI, age
DOI:10.5055/jom.2010.0022

ArticleObservations of medication compliance by measurement of urinary drug concentrations in a pain management population

AbstractBackground: One of the major concerns of physicians treating pain patients with opioids is to determine whether the patients are compliant, and this is commonly determined by urine drug testing. There is limited information on which drugs these patients are most compliant with. There is also limited information as to how compliance is defined in terms of cutoffs.
Objective: To compare reported patient medication use with the presence of the drug in the patients’ urine with defined cutoffs.
Method: A retrospective study of the medications listed by the physicians’ offices and the confirmed drug test findings. A Millennium Laboratories database of 20,457 patient results was examined for the presence of the listed medications and was matched for the presence of the drugs above the analytical cutoffs.
Results: For oxycodone and hydrocodone, the authors observed 23 and 24 percent noncompliance, respectively. For carisoprodol, they observed 33 percent noncompliance. For morphine, they observed 14 percent noncompliance. For methadone, they observed 9 percent noncompliance.
Conclusions: Noncompliance is prevalent in this patient population and varies with the prescribed drug.
Keywords: pain patients, medication compliance, opioids, carisoprodol
DOI:10.5055/jom.2010.0023

ArticleRationales behind the choice of administration form with fentanyl: Delphi survey among Danish general practitioners

AbstractBackground and Aim: The aim of this study was to describe the rationale behind the choice of fentanyl administration forms among Danish general practitioners (GPs).
Methods: Thirty-eight Danish GPs were contacted via an Internet survey system to perform a Delphi survey. In the brainstorming phase, the main reasons for prescribing and not prescribing fentanyl patches, oral transmucosal systems (OTFCs), and nasal sprays were identified. In the second phase, GPs were asked to rate the importance of each reason.
Results and Discussion: Thirty-three GPs responded in the brainstorming phase, and 33 and 31 in two rating rounds, respectively. The most important reason to choose fentanyl patches was that patients’ clinical condition did not allow them to take analgesia orally. OTFCs were primarily seen as a self-administrative alternative to injections in case of breakthrough pain. The main reasons for not choosing OTFCs were intolerance to fentanyl and price. The most important possible rationale to choose fentanyl nasal spray was easy administration. The most important possible reasons to not choose fenanyl nasal spray were application side effects.
Conclusions: The rationale behind the choice of administration form with fentanyl partly differed from those overviewed in the literature. Fentanyl nasal spray was seen as a better option for treatment of breakthrough pain among terminally ill patients if compared with OTFCs.
Keywords: fentanyl, administration, rationale, general practitioners
DOI:10.5055/jom.2010.0024

AbstractOpioid analgesia is the mainstay of treatment for moderate to severe acute and chronic pain and is highly effective in relieving pain but can be limited by side effects, the most common of which affect the gastrointestinal (GI) and central nervous systems. A growing body of evidence demonstrates that opioid-associated GI side effects constitute an important health problem with significant humanistic and economic consequences that warrant consideration by healthcare professionals and administrators in optimizing patients’ pain management. This article documents the frequency of opioid-associated GI side effects and describes its clinical and economic burdens based on a systematic review of the medical literature between 1966 and 2008.
Keywords: opioid, analgesic, side effect, burden, economic, quality of life, cost
DOI:10.5055/jom.2010.0025

AbstractFentanyl transdermal patches (FTPs) have been used for many years in the treatment armamentarium for chronic pain. By design, FTPs release drug into the skin at a constant rate and thereby provide drug in a fashion similar to continuous intravenous infusion without the disadvantages of a venous catheter and the constant presence of an analgesia pump. Pediatric patients may require doses of FTP other than the five commercially available strengths. Application of a partial FTP allows for more flexibility in dosing. Yet, very little information is provided in the literature to suggest a procedure for applying partial FTP. A technique of using a partially occluded FTP is presented in an effort to encourage further study of this and perhaps other techniques.
Keywords: fentanyl transdermal patch, pain, partially occluded patch, gradual titration
DOI:10.5055/jom.2010.0026

ArticleReview article. Hydrocodone: Does it have a role in palliative care?

Eric Prommer, MDJuly/August 2010; pages 295-299

AbstractHydrocodone is an epoxy-methoxy-methylmorphinan semisynthetic opioid (6-deoxy-3-O-methyl-6-oxomorphine hydrogen tartrate hemipentahydrate), which is structurally related to codeine, and is classified as a step 2 opioid on the World Health Organization’s stepladder for pain. Hydrocodone is typically found in fixed dose combination with acetaminophen and is often used for pain management. Hydrocodone is a heavily prescribed drug and it is important to understand the evidence base that is guiding this use. This article reviews the pharmacodynamics, pharmacology, and evidence base for the use of hydrocodone in palliative care.
Keywords: opioids, hydrocodone, cytochrome oxidase, dyspnea, pain
DOI:10.5055/jom.2010.0027

AbstractBackground: The introduction of newly formulated extended release (ER) morphine with sequestered naltrexone (Embeda) has provided another treatment option for moderate to severe persistent pain. Embeda was designed to be an abuse-deterrent opioid formulation. Naltrexone is a centrally acting opioid receptor antagonist that blocks the action of opioid. When taken as directed, insignificant amount of sequestered naltrexone would reach systemic circulation, but upon tampering, the released naltrexone may blunt the euphoria of opioids, and possibly precipitate opioid withdrawal in opioid-dependent patient.
Objective: To describe a case report of a 50-year-old opioid-dependent male who developed acute opioid withdrawal after taking crushed Embeda.
Case report: A 50-year-old male with severe, chronic low back pain due to degenerative disc disease was referred to our clinic for pain management. He was taking ER oxycodone 80 mg tid and Roxicodone 30 mg qid prn, with inadequate pain relief. A trial of ER oxymorphone was decided, at 40 mg 1-2 doses bid. The patient returned to the clinic 1 week early, out of his ER oxymorphone. At this time, the decision to switch him to Embeda was made, at 80 mg/3.2 mg, 1-2 doses bid. The patient and his family members were counseled about risk involved with tampering with Embeda. A few hours later, our clinic was informed that the patient was brought to emergency room by ambulance, in severe opioid withdrawal. He was treated with IV fluid, antiemetics, clonidine, and IV hydromorphone. His condition improved and he was discharged home the next morning. Later on, the patient admitted that he took two prescribed Embeda within half an hour, the 1st one whole and the 2nd one crushed. He further admitted that he did so against our medical advice.
Conclusion: Taking tampered Embeda may precipitate opioid withdrawal in opioid-tolerant patient. To the best of our knowledge, this is the first report of induced opioid withdrawal following consumption of crushed Embeda.
Keywords: morphine, naltrexone, opioid withdrawal, Embeda
DOI:10.5055/jom.2010.0028

AbstractObjective: To assess the long-term safety, tolerability, and consistency of effect of fentanyl pectin nasal spray (FPNS) in patients with breakthrough cancer pain (BTCP).
Design: A multicenter, open-label study.
Patients: Patients with chronic cancer pain treated with = 60 mg/d oral morphine or equivalent experiencing 1-4 episodes per day of BTCP.
Intervention: All patients entered into a 16-week treatment phase after undergoing a dose-titration phase with FPNS.
Main outcome measures: Safety and tolerability were assessed by adverse events (AEs) and by nasal tolerability assessments. Consistency of effect was monitored through additional rescue medication use and FPNS dose change.
Results: Four hundred three patients were included in the safety analyses. Of these, 356 patients entered the treatment phase and 110 patients completed the study. FPNS was self-administered for 42,227 episodes. During the treatment phase, 99 patients (24.6 percent) reported treatment-related AEs; most were mild or moderate and typical of opioids. Serious AEs were reported by 61 patients (15.1 percent), but only five were considered related to study drug. Of the 80 deaths that occurred during this study, one was assessed as possibly related to study drug. Nasal assessments revealed no significant local effects. No additional rescue medication was required after 94 percent of FPNS-treated episodes. More than 90 percent of patients required no increase in their initial dose of FPNS.
Conclusions: FPNS use for BTCP was associated with AEs, typical of opioids, with no evidence of nasal toxicity. A large proportion of BTCP episodes were treated with a single dose, and doses remained stable over the 4-month period.
Keywords: fentanyl, breakthrough cancer pain, intranasal
DOI:10.5055/jom.2010.0029

ArticleA double-blind, placebo-controlled study of dual-opioid treatment with the combination of morphine plus oxycodone in patients with acute postoperative pain

AbstractObjective: Animal and human studies suggest that coadministration of two opioids with different receptor binding properties may result in enhanced analgesia and fewer opioid-related adverse events (AEs). Q8003 (MoxDuo®), an oral dual-opioid formulation with a fixed ratio (3:2) of morphine and oxycodone, was evaluated for analgesic effects and safety in the management of acute moderate to severe pain.
Design: Randomized, double-blind, placebo-controlled, ascending-dose cohort, dose-response study with flexible dosing.
Setting: Private clinic.
Patients: Adults undergoing unilateral bunionectomy surgery. Following surgery, patients were required to have moderate or severe intensity pain on a 4-point Likert scale and =4 on an 11-point Numerical Pain Rating Scale to continue in the study.
Interventions: Q8003 was administered in four ascending-dose cohorts of 3/2, 6/4, 12/8, and 18/12 mg during the 48-hour period following surgery.
Main Outcome Measures: Sum of the pain intensity differences from baseline over 48 hours (SPID48), percentage of responders, and use of ibuprofen.
Results: Of 263 patients, 256 were randomly assigned to treatment. In patients treated with Q8003, 12 to 18 percent withdrew before study completion versus 30 percent on placebo. The mean dose of morphine/oxycodone per 6-hour period and the mean interdose interval (hours) was 6/4 mg (2.9), 9.8/6.5 mg (4.1), 11/7.5 mg (6.8), and 15/10 mg (6.6) for the 3/2-, 6/4-, 12/8-, and 18/12-mg groups, respectively. The mean SPID48 was significantly greater with each Q8003 dose when compared with placebo (p = 0.0017 for all doses versus placebo). The 12/8-mg group (11/7.5 mg/6 h) had the greatest percentage of patient responders (76 percent; p < 0.001 versus placebo) and required the fewest daily doses of ibuprofen. AEs were typical of those associated with opioid use, with the highest occurrence for nausea (38-65 percent) and low rates of somnolence (2-8 percent). Minimal or no changes in respiration and blood oxygenation were observed and euphoria was not reported.
Conclusions: The 12/8 mg dose of Q8003, an immediate-release formulation, provided the optimal combination of analgesic efficacy and tolerability, with the 3/2 and the 6/4 mg doses being an effective alternative for treatment.
Keywords: opioid, morphine, oxycodone, bunionectomy, postoperative pain, acute pain
DOI:10.5055/jom.2010.0030

ArticleReference intervals: A novel approach to detect drug abuse in a pain patient population

AbstractBackground: Pain physicians have few objective ways of determining which of their patients are drug abusers. Traditionally, these include psychological tests, physical examination, patient history, and urine drug testing. The traditional urine drug testing information provided to pain physicians mainly identifies patient compliance or drug diversion with qualitative information, that is, the patient is positive or negative for the presence of the drug in excreted urine. Although this information is useful for establishing compliance and identifying diversion, it is incomplete because it does not identify drug abuse.
Objective: The authors endeavored to determine whether quantitative urine drug testing and mathematical estimators of the upper limits of excretion could be used to identify possible drug abusers.
Study Design: Analysis of quantitative urine drug tests and application of mathematical models for reference interval estimation of common analytes to determine whether they could be used to define upper 97.5 percentile limits of excretion in the pain patient population.
Methods: The authors analyzed 8,971 consecutive urines from patients on chronic opioid therapy using nonparametric, parametric, robust, and transformed estimators to derive the upper 97.5 percentile concentration values of 31 drugs and their metabolites.
Results: The authors showed that the mathematical models used to define reference intervals could be applied to urinary drug excretion. As an example, an upper limit of excretion of approximately 100,000 ng/mL was established for morphine. Limitations of the study included lack of information on medication history, time of last dose before urine collection, age, sex, and complete medical history. Better estimates of the upper limits of excretion can be obtained by physicians applying their knowledge of dosage and collection times.
Conclusions: Application of a reference interval model allows identification of a patient population that excretes extremely high amounts of drug or its metabolite when compared with the rest of the population. Explanations for this high excretion include high dosage medication by prescription and drug abuse, determination of which can be done by the treating physician. The authors suggest that this patent-applied-for analytical model can become a potential tool to alert physicians to patients who may be abusing drugs.
Keywords: reference interval, morphine, drug abuse, upper limits of excretion, pain patients, drug testing
DOI:10.5055/jom.2010.0031

AbstractThe steady-state pharmacokinetics of an extended-release formulation of hydromorphone, OROS® hydromorphone, was investigated in a randomized, openlabel, crossover study in healthy volunteers. Participants were randomly assigned to receive 16 mg of OROS hydromorphone once daily and 4 mg of immediaterelease hydromorphone four times daily for five consecutive days. The two treatments were separated by a washout period of 7-14 days. Naltrexone was given throughout both treatment periods to block the opioid effects of hydromorphone. Steady-state hydromorphone concentrations were statistically analyzed using Helmert contrasts to determine when steady state was reached. A total of 30 participants were enrolled, of whom 29 completed both treatment periods. The two treatments produced comparable steady-state plasma drug concentrations, but peakto- trough fluctuations were smaller with OROS hydromorphone (61 percent vs 172 percent) in comparison with immediate release hydromorphone. Overall systemic exposure to hydromorphone was similar between the two formulations. The ratio of the geometric means between the two formulations for the area under the concentration-time curves at steady state was 105.2 percent with a 90% confidence interval (CI) of 99.8-110.8 (geometric mean: 102.7 percent; 90% CI: 97.6-108.2 after correcting for measured drug content), which was within the bioequivalence range (80-125 percent). The analysis of Helmert contrasts showed that steady state conditions were attained by day 4. Both treatments were well tolerated. This study shows that OROS hydromorphone maintains steady-state plasma drug concentrations within the same range as immediate-release hydromorphone at the same total daily dose, with less fluctuation.
Keywords: OROS hydromorphone, extended-release hydromorhphone, pharmacokinetics, opioids, osmotic pump
DOI:10.5055/jom.2010.0032

AbstractObjectives: The authors sought to analyze the relationship between financial discharge from methadone maintenance therapy (MMT) and subsequent involvement in the criminal justice system among individuals receiving state-subsidized MMT slots and individuals who were financially discharged from MMT.
Methods: The authors examined state-level client treatment records from all individuals who were on a subsidized MMT slot and all individuals who were discharged due to their inability to pay (financial discharge) from one of the three MMT programs during an 18-month period. The authors cross-referenced these records, through a state-managed database, with records of the Department of Corrections.
Results: Individuals in the control group had longer durations of stay in MMT and fewer other kinds of treatment admissions during the study period. An 81 percent of individuals in the financially discharged group received other treatment episodes versus 0.3 percent in the control group (p < 0.001). More than twice the number of individuals financially discharged from MMT were incarcerated during the study period when compared with the control group (67 percent vs 33 percent, p < 0.001). In logistic regression analysis, individuals in the control group had 0.26 times the odds of incarceration when compared with individuals financially discharged from MMT (95% CI: 0.09-0.73).
Conclusions: MMT has been shown to reduce involvement in the criminal justice system, yet cost of MMT continues to inhibit its accessibility. Our data suggest that removal of cost as a barrier to access MMT may facilitate longer treatment duration and minimize involvement with the criminal justice system.
Keywords: methadone maintenance therapy, financial discharge, incarceration
DOI:10.5055/jom.2010.0034

AbstractThe administration of opioid analgesics via the intrathecal route is becoming more commonplace for a variety of chronic nonmalignant pathologic pain states. Despite this growing trend, there is very little information available to guide practitioners with regard to patient selection as well as intrathecal drug dosing paradigms. The authors describe the use of a protocol for patient selection, including pretrial preparation, as well as detailed very low-dose chronic intrathecal morphine dosing regimens to treat patients with refractory chronic nonmalignant pain.
Keywords: intrathecal morphine, intrathecal drug delivery, low-dose opioid, chronic nonmalignant pain, intrathecal analgesics
DOI:10.5055/jom.2010.0035

AbstractTreatment with opioid medications has grown over the past decades, but has been surrounded by some ongoing controversy and debate to whether it is causing more harm than good for patients. To this end, the field of pain management has suffered from a lack of clarity about some basic definitions on concepts such as tolerance and hyperalgesia. Some characterize these issues as inevitable parts of opioid therapy while other schools of thought look at these issues as relatively rare occurrences. Unfortunately, most of the rhetoric around these topics has occurred with very little in the realm of real world data. To this end, the authors have reviewed the charts of 197 patients treated by a pain specialist for at least 1 year to better illustrate whether notions of tolerance and hyperalgesia are common occurrences and, more importantly, whether they occur within any type of specified timeframe. A total of 197 patient charts were reviewed. The sample had an average age of 49.39 years (range = 19-87 years; standard deviation [SD] = 12.48) and comprised 66 men (33.5 percent) and 131 women (66.5 percent). The patients were seen in the pain practice for an average of 56.52 months (range = 12-155 months; SD = 31.26). On average, the patients maintained an average daily dose of 180 mg morphine equivalents for a period of 35.1 months (range = 3-101 months; SD = 21.3). Looking at the pattern of medication usage change over time, 34.5 percent experienced dose stabilization after the initial titration, 13.2 percent had early dose stabilization within one dose change, and an additional 14.7 percent actually had dose decreases after surgeries or other interventional procedures. Only 6.6 percent of the sample had to be discharged or weaned from controlled substances over time in the clinic. Thus, it appears that tolerance and hyperalgesia are not foregone conclusions when considering placing a patient on long-term opioid therapy.
Keywords: tolerance, dependence, opioids, hyperalgesia, long-term opioid therapy
DOI:10.5055/jom.2010.0036

AbstractBackground: The aim of this retrospective study is to compare safety and efficacy of postoperative epidural butorphanol/bupivacaine with the gold-standard epidural analgesic infusion fentanyl/bupivacaine in children.
Methods: With the Institutional Review Board’s approval, the authors searched their Pain Management Database and divided children who received epidural analgesia into two groups. Each butorphanol group subject was matched with two fentanyl group subjects. Demographic data, pain scores, epidural interventions, epidural side effects, use of rescue opioid analgesia and adjuvant analgesics, causes of epidural failure, time of first oral intake and ambulation, and length of stay were statistically compared.
Results: A total of 191 patients were identified between 2000 and 2007; 58 in epidural butorphanol/bupivacaine and 133 in fentanyl/bupivacaine groups. Demographic data were comparable between the groups. The number of children with good pain control on postoperative days 1 and 2 in butorphanol (84 and 82 percent) and fentanyl (93 and 91 percent) groups were statistically similar (p = 0.06 and 0.13, respectively). Incidences of epidural side effects, especially pruritus, were significantly higher in the fentanyl group. Significantly more children in the butorphanol group required epidural rate changes when compared with those in the fentanyl group. Incidence of failed epidurals was significantly higher in the fentanyl group when compared with that in the butorphanol group. Clinically significant respiratory depression occurred in two children in the fentanyl group and in none of the children in the butorphanol group (p > 0.99).
Conclusions: Epidural butorphanol provided similar analgesia to epidural fentanyl after urological procedures in children, but butorphanol caused less pruritus than fentanyl.
Implication statement: Epidural analgesia with butorphanol/bupivacaine is effective in children undergoing urological procedures. When compared with epidural fentanyl, epidural butorphanol causes significantly less itching.
Keywords: epidural, butorphanol, pediatric
DOI:10.5055/jom.2010.0037

AbstractTwenty-nine opioid-exposed and 26 nonopioid-exposed neonates received neonatal abstinence syndrome (NAS) assessment by an examiner blinded to group status twice daily over the first two postnatal days. The opioid-exposed group had higher mean NAS scores than the nonopioid-exposed group. A 3-sign index, consisting of hyperactive moro reflex, mild tremors when undisturbed, and increased muscle tone, showed excellent discrimination between groups. The use of a 3-sign screening index in the days immediately after birth may provide a cost-effective mechanism for the identification of opioid-exposed infants, particularly in infants of women for whom identification of status as a substance user may not be immediately evident. Although a potentially useful screening tool, the 3-sign screening tool should not replace the full assessment of the opioid-exposed infant after birth.
Keywords: neonate, methadone, substance abuse, pregnancy, women
DOI:10.5055/jom.2010.0038

ArticleImproved detection of ethyl glucuronide and ethyl sulfate in a pain management population using high-throughput LC-MS/MS

AbstractBackground: Ethyl glucuronide (EtG) and ethyl sulfate (EtS) have been proposed as markers for detecting alcohol use because they exhibit extended excretion lifetimes when compared with ethanol; however, their presence is not considered as absolute proof of alcohol use. Two methods are currently used for the detection and quantitation of EtG: immunoassay and mass spectrometry. The purpose of this study was to provide more patient data to better compare the two methods.
Methods: A retrospective diagnostic accuracy study was performed to compare the methods. EtS was also measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) as an additional comparative analyte. The investigators examined 4,287 sequential urines from pain patients to determine the incidence of alcohol use and the corresponding presence of EtG by immunoassay at a cutoff of 500 ng/mL. EtG and EtS were subsequently quantitated in all the urines using LC-MS/MS.
Results: A total of 794 samples were found positive by immunoassay, and these results were compared at three distinct LC-MS/MS cutoffs of 100, 500, and 1,000 ng/mL. The incidence of ethanol use in this population was found to be at least 12 percent.
Conclusions: Approximately 30 percent of the samples screened by immunoassay as positive were confirmed to be negative by LC-MS/MS.
Keywords: ethyl glucuronide, ethyl sulfate, pain patients, alcohol abuse, immunoassay, LC-MS/MS
DOI:10.5055/jom.2010.0039

ArticleCerebral measurements and their correlation with the onset age and the duration of opioid abuse

AbstractBackground: Opioid-dependent patients have been shown to have structural brain alterations. This study focuses on magnetic resonance imaging (MRI) measurements of brain and their correlation with the onset age and the duration of opioid abuse.
Methods: Brain MRI was obtained from 17 opioid-dependent patients (mean age 34 years, SD 7 years) and 17 controls. Compulsive opioid use had begun between ages 15 and 31 (mean 20) and had continued from 5 to 26 years. All patients were tobacco smokers, six had also abused amphetamines and 11 benzodiazepines. Relative volumes of cerebral white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) spaces were measured. In addition, Sylvian fissure ratio (SFR), bifrontal ratio, and midsagittal cerebellar vermian area were correlated with the onset age and the duration of opioid abuse.
Results: The total volume (GM + WM + CSF) of the cerebrum was significantly smaller in patients than in controls (Mann-Whitney U-test, p = 0.026) as well as the absolute volumes of GM and WM (p = 0.014 and p = 0.007, respectively). There was no significant difference in GM and WM volumes normalized with total cerebral volume. In contrast, the absolute volume of CSF did not significantly differ between the groups, but the relative volume of CSF was significantly higher in opioid dependents (p = 0.029). SFR and bifrontal ratio were larger in opioid dependents than in controls (p = 0.005 and p = 0.013). The SFR correlated negatively (p = 0.017, r = -0.569) and the area of vermis cerebelli correlated positively (p = 0.043, r = 0.496) with the onset age of opioid abuse. The length of opioid abuse and the area of vermis cerebellum had a negative correlation (p = 0.038, r = -0.523) even though the areas of cerebellar vermis did not significantly differ between opioid dependents and controls. The authors speculate that the onset of substance abuse in adolescence or early adulthood may have in part disturbed the late brain maturation process, as in normal development, the dorsolateral frontal cortex and superior parts of the temporal lobes are the last to maturate. Also, the cerebellar vermis may be affected by early onset substance abuse. It is possible that the brain is more vulnerable to substance abuse at a young age than later in life.
Keywords: MRI, Sylvian fissure ratio, brain, opioid dependence, imaging, neuropsychological tests
DOI:10.5055/jom.2010.0040

AbstractMorphine, oxycodone, and fentanyl are major opioids available as controlledrelease morphine (CRM), controlled-release oxycodone (CRO), and transdermal fentanyl (TDF), respectively, in Japan. The authors conducted a retrospective chart review to examine (1) nausea and somnolence on commencement of CRM, CRO, and TDF for cancer pain treatment, (2) the antiemetic effectiveness of prochlorperazine to prevent opioid-induced nausea, and (3) the side effect of prochlorperazine on somnolence in patients with cancer pain. Four hundred thirteen patients with cancer were prescribed with CRM (N = 66), CRO (N = 196), and TDF (N = 151). The incidence of nausea on commencement of the TDF group (6.8 percent) was significantly lower than that of both the CRM group (22.6 percent) and the CRO group (35.4 percent; p < 0.001). There was no significant difference in the incidence of nausea on commencement of all groups combined with prochlorperazine at dosage of 15 mg/d. The incidence of somnolence on commencement of the TDF group (9.0 percent) was significantly lower than that of both the CRM group (31.3 percent) and the CRO group (41.5 percent; p < 0.001). The incidence of somnolence on commencement of the CRO group combined with prochlorperazine was significantly higher than that of the CRO combined without prochlorperazine (p < 0.05). In conclusion, the incidence of nausea and somnolence on commencement of TDF are significantly lower than that of both CRM and CRO for cancer pain treatment. Prochlorperazine at a dosage of 15 mg/d may not be effective in preventing opioid-induced nausea and may cause somnolence in patients with cancer pain.
Keywords: opioid-induced nausea, opioid-induced somnolence, morphine, oxycodone, fentanyl, prochlorperazine, side effect, opioid
DOI:10.5055/jom.2010.0041

ArticleCurrent concepts in the management of opioid-induced constipation

AbstractPatients with chronic pain on daily opioid therapy are frequently burdened with symptoms of constipation. Opioid-induced constipation (OIC) contributes to an overall negative impact on the quality of life and may result in poor pain management outcomes. Laxative agents are crucial in opioid-related pain management. Following a careful assessment, a stepwise approach to OIC may provide comfort and relief to patients. This article reviews the pathophysiology, assessment, and pharmacological treatment of OIC. Novel approaches for OIC such as the peripheral opioid receptor antagonists and selective serotonin antagonists are also discussed.
Keywords: constipation, laxatives, symptom management
DOI:10.5055/jom.2010.0042

ArticleThe relationship between opioid and sugar intake: Review of evidence and clinical applications

AbstractOpioid dependence poses significant public health risks arising from associated morbidity and mortality caused by accidents, infectious diseases, and social ramifications of crime and unemployment, among other complications. Opioid use, acute and chronic, is also associated with weight gain, glycemic dysregulation, and dental pathology. The literature supporting the connection between opiate use and development of preference for sweet tastes is reviewed, and further association with dental pathology, weight gain, and loss of glycemic control are considered. Additionally, the impact of sweet tastes on the endogenous opioid system, as pertaining to analgesia, is also discussed. The authors discuss the clinical implications in relation to the aforementioned conditions while treating the opiate-dependent patient.
Keywords: opioid, sugar, weight gain, diabetes, analgesia
DOI:10.5055/jom.2010.0043